There is an unmet need to inhibit the key cancer promoting transcription factor MYC (both c-MYC and MYCN) that act downstream of many cell receptors and signal transcription pathways to activate genes for cancer cell resistance and tumor growth. To date, small molecule inhibitors of MYC have remained elusive. In our Phase I STTR (CA192656), we developed a lead compound, SF2523 which displays potent orthogonal inhibitory activity against MYC by blocking PI-3 kinase (PI-3K) and the highly dominant regulator of epigenetic machinery, BRD4. The objective of this application will be to develop SF2523 through advanced preclinical studies for therapeutic application in this Phase II STTR proposal. The transcription factor, MYC (c-MYC and MYCN) plays a key role in cancer growth, proliferation, survival, and it is overexpressed in a subgroup of most human cancers resulting in resistance to PI-3K and other signaling pathway inhibitors. Both MYC and PI-3K are well-established onco-proteins that are confirmed drivers in a large number of tumor types. Moreover, BRD4 is rapidly emerging as a dominant epigenetic regulator of the transcriptome and of cancer cell resistance to kinase inhibition. Therefore, there is general consensus in the cancer biology arena that inhibition of BRD4 and/or MYC should prove beneficial in multiple cancers where MYC is an established regulator of tumor cell transformation and resistance. Our innovative approach centers on our central hypothesis that a dual PI-3K/BRD4 inhibitor, SF2523, will potently inhibit MYC activity by enhancing its degradation via PI-3K inhibition AND blocking MYC transcriptional activity via BRD4 inhibition. Our Phase I STTR Specific Aims successfully solved the crystal structure of SF2523 in the active site of BRD4 and determine the structure activity relationships around dual PI-3K/BRD4 inhibitors designed by validated molecular modeling studies and demonstrated the safety of our dual-targeting single inhibitor versus the accumulated toxicity of using two separate inhibitors. Our successful Phase I studies set the stage for our selection of SF2523 as the candidate for preclinical development to treat PI-3K/MYC dependent malignancies in Phase I trials as a clinical development strategy. The significance of this Phase II proposal is that it will advance SF2523 through preclinical development and validate this novel dual PI-3K/BRD4 inhibitor as a drug candidate against PI-3K/MYC-driven malignancies with high mortality rates e.g. hepatocellular carcinoma (HCC) and squamous cell carcinoma of the head/neck (SCCHN) and obtain a back-up candidate by further evaluation of SF2523 analogs found from Phase I SAR studies. Moreover, our aims in Phase II will identify PI-3K and MYC tumor signatures and a companion diagnostic approach which will define sensitivity to SF2523 as we move toward FDA registration and commercialization of this ?first in class? dual PI-3K/BRD4 inhibitor chemotype in cancer therapeutics.